The present invention, in some embodiments thereof, relates to peptides derived from extracellular signal-regulated kinase1/2 (ERK) which may be used for treating cancer.
The extracellular signal-regulated kinase1/2 (ERK) cascade is an intracellular signaling pathway that regulates cellular processes, such as proliferation and differentiation. Being a central signaling component, its dysregulation is involved in various pathologies, particularly cancer. Indeed, inhibitors of both Rafs and MEK1/2 within the cascade were recently developed, but despite the widespread involvement of ERK in the induction and maintenance of cancers, these inhibitors were proven beneficial almost only in B-Raf mutated melanomas. In addition, most sensitive melanomas develop resistance to the Raf/MEK inhibitors within several months of treatment. The lack of effect in many cancer types, and the mechanisms of acquired resistance are now being investigated, and shown to often involve the inhibition of ERK-dependent negative feedback loops. Consequently, this inhibition allows hyperactivation of upstream signaling components that circumvent the inhibited ERK cascade. Hence, inhibiting the ERK cascade without affecting the feedback loops should result in a more general anti cancer drug.
One of the key steps in the transmission of extracellular signals is the nuclear translocation of ERK. In resting cells, most of ERK is localized in the cytoplasm due to anchoring to cytoplasmic proteins, but stimulation causes a rapid and massive nuclear translocation of a large portion of the ERK molecules. The molecular mechanism of translocation involves first TEY-phosphorylation-dependent conformational change, which results in the detachment of the ERK molecules from their anchors. This exposes the ERK to an additional phosphorylation on two Ser residues within a nuclear translocation signal (NTS). The phosphorylation of the NTS then allows the beta-like importin (Imp), Imp7, to bind it, and consequently, induce the nuclear translocation of the kinases. This rapid translocation allows the phosphorylation and activation of many nuclear proteins, which are important for the induction and regulation of cellular processes.
U.S. Patent Application Publication No. 20100099627 teaches 18 amino acid peptides that are capable of preventing ERK translocation into the nucleus.